Thiophene derivatives

ABSTRACT

Thiophene derivatives wherein the thiophene ring is linked by oxygen, sulfur, a carbonyl group or a carbon-carbon bond to a phenyl ring which is substituted by a haloalkylsulfonamido group, and the sulfonamido nitrogen atom is optionally substituted. These compounds are active anti-inflammatory agents.

United States Patent Harrington et al. [4 1 Oct. 3, 1972 [54] THIOPHENE DERIVATIVES [56] References Cited [72] Inventors: Joseph Kenneth Harrington, Edina; UNITED STATES PATENTS George G Moore, Birchwood; 3,576,866 4/1971 Robertson et al. ..260/556 John F. Gerster, Woodbury, all of 3,558,640 1/1971 Shen et al. ..260/294.8 Minn. 3,476,766 11/1969 Brown ..260/302 I 3,429,911 2/1969 Kirchner et a] ..260/465 [73] Assgnee' 32 iT' 3,317,543 5/1967 Humber ..260/290 age, 3,312,730 4/1967 Winter etal ..260/473 [22] Filed: April 13, 1970 Primary Examinerl-Ienry R. Jiles PP N05 28,150 Assistant ExaminerCecilia M. Shurko Attorney-Kinney, Alexander, Sell, Steldt & Delahunt [52] US. Cl ..260/332.3 C, 71/90, 260/329 AM,

260/329 5, 260/332.2 R, 260/332.3 R, [57] ABSIRACT 260/3325, 424/275 Thiophene derivatives wherein the thiophene ring is [51] Int. Cl. ..A61k 27/00, C07d 63/12 linked by oxygen, sulfur, a carbonyl group or a car- [58] Field 61 Search .....260/332.3 c, 332.5, 332.2 R, boll-carbon bond to a p y ring which is substituted 260/332'3 R by a haloalkylsulfonamido group, and the sulfonamido nitrogen atom is optionally substituted. These compounds are active-anti-inflammatory agents.

13 Claims, No Drawings THIOPHENE DERIVATIVES This invention relates to thiophene derivatives in which the thiophene ring is linked by oxygen, sulfur, carbonyl or a carbon-carbon bond to a phenyl ring which is substituted by a haloalkylsulfonamide group in which the sulfonamido nitrogen atom is optionally substituted. For convenience, they may also be referred to as substituted thiophenes. These compounds are active anti-inflammatory agents and some are also antimicrobial agents and herbicides.

It is an object of the invention to provide compounds which are anti-inflammatory agents.

It is an object of theinvention to provide compounds for the control of microbes.

It is another object of the invention to provide compounds which modify the growth of plants, i.e., which prevent, alter, destroy or otherwise affect the growth of plants.

It is a further object of the invention to provide a method for controlling inflammation in mammalian tissue.

It is a further object of the invention to provide a method for controlling micro-organisms.

It is a further object of the invention to provide a method for controlling unwanted plants.

It is still another object of the invention to provide anti-inflammatory compositions containing one or more substituted thiophenes as active ingredients therein. v

It is still another object of the invention to provide anti-microbial compositions containing one or more substituted thiophenes as active ingredients therein.

It is still another object of the invention to provide herbicidal compositions containing one or more substituted thiophenes as active ingredients therein.

Still other objects will be made apparent by the following specification.

DETAILED DESCRIPTION According to the present invention, there is provided a class of compounds of the formula:

mom A 8 Lt S wherein R is lower haloalkyl and at least one halogen is bonded to the alpha carbon atom or at least two halogens are bonded to a beta carbon atom,R is hydrogen, a pharmaceutically acceptable cation, lower alkyl (preferably containing from one to three carbon atoms), cyano, lower alkylsulfonyl, fluoromethylsulfonyl or a member of the group represented by the formula wherein A is --O-, -S-,

or a single carbon-carbon bond and Q is a hydrocarbon group containing up to 14 carbon atoms, m is one or two, Y is hydrogen, lower alkyl, lower alkoxy, halogen or hydroxy, Y' is hydrogen, lower alkyl or halogen and Z is carbonyl, O, S or a single carbon-carbon bond.

The term lower when applied to substituent groups (radicals) of this invention, such as alkyl, alkoxy, alkylsulfonyl and haloalkyl, refers to groups containing one to about four carbon atoms.

R, can be straight or branched chain perhaloalkyl or partially halogenated alkyl, and the halogens can be fluorine or chlorine, preferably fluorine. As noted previously, R, should have at least one halogen bonded to the alpha carbon atom, or if there is no halogen bonded to the alpha carbon atom at least two halogens bonded to the beta carbon atom. The haloalkyl radicals may contain only one type of halogen, or the halogens may be mixed. When they are mixed it is preferable to have one or more fluorine atoms per chlorine atom. Most preferred are compounds wherein R is trifluoromethyl or difluoromethyl since these are generally most active as anti-inflammatory agents.

The compounds of the invention are acidic in nature when R is hydrogen. Consequently, they form salts, i.e., compounds of Formula I wherein R is a pharmaceutically acceptable cation. These are generally alkali metal (e.g., lithium, sodium and potassium), alkaline earth metal (e.g., barium, calcium and magnesium),

ammonium and amine salts.

The amine salts include the salts of aliphatic (e.g., alkyl) and aromatic amines, primary, secondary and tertiary. Preferred among the pharmaceutically acceptable salts are those in which R is an amine cation. The salts can be prepared by treating the acid form (wherein R is hydrogen) with a stoichiometrically equivalent amount of an appropriate base under mild conditions. Among the metal salts of the invention are alkali metal (e.g., lithium, sodium and potassium), alkaline earth metal (e.g., zinc and iron) salts as well as other metal salts such as aluminum.

Since many of the salts are water soluble, they are often used in the form of aqueous solutions. Also, they can be used in making pharmaceutical preparations in the form of capsules for oral administration.

Compounds of the invention wherein R is hydrogen or a pharmaceutically acceptable cation are generally active as anti-inflammatory agents. The compounds in which R is a pharmaceutically acceptable cation sometimes provide advantages such as improved absorption, desirable solubility and stability characteristics.

Compounds wherein R is alkyl cyano, alkylsulfonyl fluoromethanesulfonyl and the group As defined above are generally less active than the corresponding compounds wherein R is hydrogen or a pharmaceutically acceptable cation, but are often less analogous compound wherein R is hydrogen, this compound may be preferred for therapeutic treatment.

In Formula I, Z is preferably carbonyl; since this link has generally provided compounds with higher anti-inflammatory activity. When either Y or Y (or both) is lower alkyl or lower alkoxy, it is preferable that it contains one or two carbon atoms and when Y or Y' is halogen it is preferably fluorine or chlorine. Also, it is preferred that the link Z be oriented meta to the haloalkylsulfonamido group, and that the link Z be bonded to the 2 position of the thiophene ring. Compounds wherein Y is hydrogen and Y is hydrogen or halogen are most preferred.

Many of the compounds of the invention are also active as anti-microbial agents (particularly those wherein R is H) or herbicides (particularly when R, is trifluoromethyl and R is H, a cation, cyano or according to standard screening methods.

Generally, to produce the compounds of Formula I wherein R is a hydrogen atom, an aniline derivative of Formula II is condensed with a haloalkanesulfonyl halide or anhydride according to the following scheme:

wherein Z, Y, Y and R are as previously defined and W represents a halogen atom, preferably fluorine or chlorine, or the corresponding anhydride grouping, OSO R F Approximately equivalent amounts of the reactants are brought together at temperatures most often ranging between about l5 and 150 C. If necessary or desirable, the reaction can be carried out in a pressure vessel. The reaction is preferably, but not necessarily, carried out in the presence of an acid acceptor such as the alkali or alkaline earth metal carbonates and bicarbonates or a tertiary amine such as pyridine, triethylamine or N,N-dimethylaniline. The amount of the acid acceptor can be varied widely; however, a mole percent excess of that amount of base sufficient to bind the liberated strong acid (HW) is routinely employed.

The condensation is usually conducted in the presence of an appropriate inert organic solvent. Typical solvents suitable for this purpose are methylene chloride, chloroform, carbon tetrachloride, benzene, toluene, 1,2-dimethoxyethane, bis( 2-methoxyethyl)ether, acetonitrile, nitromethane, N,N- dimethylformamide and the like.

After reaction is complete, if the reaction solvent is not water miscible, the product mixture can be extracted with a dilute aqueous base solution. The product, in the form ofa salt which is usually soluble in the aqueous layer, is precipitated therefrom by addition of a mineral acid such as hydrochloric or sulfuric acid, and collected by filtration. Alternatively, the product mixture can be washed with aqueous hydrochloric acid, the solvent evaporated in vacuo, and the residue dissolved in a dilute aqueous base solution which is washed with dichloromethane and treated with decolorizing charcoal. The product is in the form of a salt and is then isolated as the free acid as described above.

If the reaction solvent is water miscible, the product is generally obtained by dilution of the reaction mixture with water. The product, a solid or oil, is separated and purified by conventional methods. The compounds prepared according to the foregoing procedures are crystalline solids or distillable liquids. The solids are purified, in general, by recrystallization from aqueous alcohol, trichloroethylene, hexane, benzene-hexane mixtures and the like. Elution chromatography has also been found to be a useful purification technique.

The salts are readily prepared by adding the stoichiometric amount of the selected base in inert solvent solution (aqueous or nonaqueous) to the acidic compound. The resulting solution is treated to remove the solvent, e.g., by evaporation under reduced pressure to obtain the salt, usually as a dry powder. Appropriate bases for use in preparing the metal salts include metal oxides, carbonates, hydroxides, bicarbonates and alkoxides. The organic amine salts and the ammonium salts can be prepared by reacting the acid form with the appropriate organic base or ammonium hydroxide. Some salts are also prepared by cation exchange reactions (by reacting a salt of the invention with an organic or inorganic salt in a cation exchange reaction).

In order to prepare the compounds of the invention wherein R is lower alkyl, one reacts compounds of formula I wherein R is a metal ion, for example sodium or potassium, with a stoichiometric amount of alkyl bromide or iodide or a dialkyl sulfate in a suitable solvent such as acetone.

Compounds of the invention wherein R is cyano are prepared by reacting the corresponding compounds of the invention wherein R is a cation such as sodium or potassium with cyanogen chloride or bromide in a nonreactive solvent.

Compounds of the invention wherein R is alkylsulfonyl or fluoromethylsulfonyl are prepared by reacting the corresponding compounds of the invention wherein R is a cation such as sodium or potassium with fluoromethanesulfonyl chloride or an alkylsulfonyl chloride.

Compounds of the invention wherein R is a if -AQm are prepared by reacting the corresponding compounds wherein R is a cation with an acylating agent of the formula la can be used in preparing the compounds of the invention, including acyl halides or anhydrides, haloformates, thiol haloformates, carbamyl/o halides and the like. These compounds are either available directly, or in the case of certain chloroformates or thiol chloroformates are easily prepared from phosgene and the appropriate alcohol or thiol.

Exemplary of the compounds of Formula I are the following:

3-( 2-thenoyl)trifluoromethanesulfonanilide; 3-(2-thenoyl)perfluoroisopropanesulfonanilide;

3 2-thenoyl )chloromethanesulfonanilide; 4-chloro-3-(5-chloro-2-thenoyl)trifluoromethanesulfonanilide; 3-(5-chloro-2-thenoyl)difluoromethanesulfonanilide; 2-( 2-thenoyl)trifluoromethanesulfonanilide; 4-(2-thenoyl)trifluoromethanesulfonanilide;

3-( 2-thienylthio)trifluoromethanesulfonanilide;

3 2-thienyloxy )trifluoromethanesulfonanilide; 3-(2-thienyl)trifluoromethanesulfonanilide; N-cyano-3-(2-thenoyl)trifluoromethanesulfonanilide; N -cyano-3-( 5-chloro-2-thenoyl )trifl uoromethanesulfonanilide;

N-methylsulfonyl-3-( 2-thenoyl )trifluoromethanesulfonanilide;

N-fluoromethylsulfonyl-3-(5-chloro-2- thenoyl)trifluoromethanesulfonanilide; N-methyl-3-(5-chloro-2-thenoyl)difluoromethanesulfonanilide;

N-ethyI-3-( 5-chloro-2-thenoyl )difluoromethanesulfonanilide;

N-ethoxycarbonyl-3-(5-chloro-2- thenoyl)trifluoromethanesulfonanilide;

N-acetyl-3 S-chloro- 2-thenoyl )trifluoromethanesulfonanilide;

N-phenoxycarbonyl-3-(5-chloro-2- thenoyl)trifluoromethanesulfonanilide; N-benzyloxycarbonyl-3-(2- thenoyl)trifluoromethanesulfonanilide; N-thiophenoxycarbonyl-3-(2- thenoyl)trifluoromethanesulfonanilide; N-octyloxycarbonyl-3-( 2-thenoyl)trifluoromethanesulfonanilide;

sodium 3-(5-fluoro-2-thenoyl)trifluoromethanesulfonanilide; potassium 3-(5-methyl-2-thenoyl)trifluoromethanesulfonanilide; 3-(5-chloro-2-thenoyl)-4-methoxytrifluoromethanesulfonanilide; 3-(5chloro-2-thenoyl)-4-hydroxytrifluoromethanesulfonanilide;

5-methyl-3-( 2-thenoyl)trifluoromethanesulfonanilide and 3-(5-chloro-2-thenoyl)2,2,2-trifluoroethanesulfonanilide.

Haloalkanesulfonyl anhydrides and halides useful as starting materials in these procedures are known to the art, for example.

fluoromethanesulfonyl chloride,

difluoromethanesulfonyl chloride,

2,2,2-trifluoroethanesulfonyl chloride,

1 ,l,2,2-tetrafluoroethanesulfonyl chloride,

2,2,3,3-tetrafluoropropanesulfonyl chloride,

2-hydroperfluoropropanesulfonyl chloride,

Formula Ill,

Z-HYI (MN 0 V S Y III by reduction of the nitro group. Methods for the reduction of aromatic nitro compounds are well known to the art. Both chemical, for exampleiron and acetic acid, sodium sulfide in ethanol, and the like, and catalytic, for example Raney nickel, palladium on charcoal, and the like, methods are used successfully to convert compounds of Formula III to compounds of Formula ll.

Some compounds of Formula I" are not known, but are prepared by known methods. The compounds of Formula III wherein Z is carbonyl are generally prepared by a Friedel-Crafts reaction between a nitrobenzoyl halide and a thiophene and those wherein Z is oxygen or sulfur are prepared by the halogen displacement reaction of a nitrothiophenol or nitrophenol with a halothiophene. This displacement reaction is generally carried out using the phenol or thiophenol compound in the form of its cuprous or alkali metal salt.

The intermediate compounds of Formula ll and Ill wherein Y is Ol-l are prepared by cleavage of the alkoxy group of comparable compounds wherein Y is alkoxy. This can be done conveniently by heating with pyridinium chloride. The intermediate compoundsof Formula III wherein Z is a carbon-carbon bond are prepared by the diazo reaction or the nitrosoacetylamine reaction (Organic Reactions, Vol. 2, page 224) from known intermediates.

As noted previously, the compounds of the invention are as a class active anti-inflammatory agents, although some are more active than others. The anti-inflammatory activity can be conveniently demonstrated using assays designed to test the ability of these compounds to antagonize the local edema which is a characteristic of the anti-inflammatory response (rat foot edema test) and to inhibit the onset of the erythematous manifestation of inflammation (guinea pig erythema test).

These are standard assays well-known to those skilled in the art. They are described in journals and other publications. Leading references to the rat foot edema test are:

l. Adamkiewicz et al., Canad. J. Biochem. Physio.

2. Selye, Brit. Med. J. 2:1 129, l949; and

3. Winter, Proc. Soc. Exper. Biol. Med. 1 1 1:544,

Leading references to the guinea pig erythema test are:

l. Wilhelmi, Schweiz. Med. Wschr. 792577, 1949,

and

2. Winder et al., Arch. Int. Pharmacodyn. 116:261,

The anti-inflammatory activity of various compounds of the invention may be detected by other standard assays known to the art such as the cotton pellet granuloma and adjuvant arthritis tests.

The compounds are administered orally, for example as 4 percent acacia suspensions, but may also be administered parenterally. Amounts are generally about 1 to 500 mg./kg. of body weight of the mammal to be treated.

Presently preferred compounds of the invention, because of high anti-inflammatory activity, are

3-( 2-thenoy1)trifluoromethanesulfonanilide,

3-(5-ch1oro-2-thenoy1)trifluoromethanesulfonanili de and 3-( 5-chloro-2-thenoyl )difluoromethanesulfonanilid The anti-microbial activity of the compounds of the invention has been evaluated using a variation of the original agar-plate diffusion method of Vincent and Vincent (e.g., see Vincent, 1.6., and Vincent, Helen W., Proc. Soc. Exptl. Biol. Med. 55:162-164, 1944, and Davis, B.D., and Mingioli, E.S., Jour. Bact. 66:129-136, 1953.

The herbicidal activity of representative compounds of Formula 1 has been determined using screening tests against experimental plantings. Both preand postemergence activity are determined in a direct screen against selected weed species. The following weed mixtures are used for the tests.

Grasses:

Giant foxtail (Setariafaberii) Barnyard grass (Echinochloa crusgalli) Crabgrass (Digitaria ischaemum) Quackgrass (Agropyron repens) Broadleaves:

Pigweed (Amaranthus retroflexus) Purslane (Portulaca oleracea) Wild Mustard (Brassica kaber) Wild Morning G1ory'(C0nv0lvulus arvensis) The test chemicals are dissolved in a small amount of acetone or other suitable solvent and then diluted with water to give a concentration of 2000 ppm. From this concentration aliquots are diluted to give a final concentration of 500 ppm. Eighty ml. of this solution are added to a 6-inch pot containing the weed seeds to give a concentration equivalent to 201b./acre.

To assess post-emergence activity, the same weed mixtures are allowed to grow from 2 to 3 weeks until the grasses are approximately 1 to 3 inches and the broadleaves 1 inches tall. They are sprayed for approximately 10 seconds or until good wetting of the leaf surfaces occurs with a 2000 ppm solution as described above.

The following examples are given for the purpose of further illustrating the procedures of the present invention, but are not intended, in any way, to be limiting on the scope thereof. Thus, while the majority of the examples relate to compounds in which R contains but a single carbon atom, other haloalkyl groups can be substituted in place thereof. Also, although the examples relate for the most part to compounds in the acid form (that is having a hydrogen atom bonded to the sulfonamido nitrogen), together with compounds representative of the sodium salts and N-alkyl compounds, it is understood that the other salts and compounds of the invention are also easily prepared and are likewise contemplated. The salts, which have a cation bonded to the sulfonamido nitrogen, generally have the utility areas of the corresponding acid-form compounds.

All melting points in the examples are uncorrected. The boiling points and melting points are given in degrees Centigrade and the pressures in millimeters of mercury.

EXAMPLE 1 This example illustrates the method for the preparation of intermediates of Formula 111 wherein Z is carbonyl.

Aluminum chloride (33.3 g., 0.25 mole) is mixed with 1,2-dich1oroethane (200 ml.) and the mixture cooled to about 5 C. A solution of 2-chlorothi0phene (29.7 g., 0.25 mole) and 3-nitrobenzoyl chloride (46.5 g., 0.25 mole) is added dropwise over a 3-hour period. The solution is allowed to warm and stand overnight at room temperature. The mixture is poured over ice, diluted with dichloromethane and filtered. The organic layer is separated, washed with sodium carbonate solution and dried over magnesium sulfate. The solvent is removed in vacuo and recrystallization from methanol gives solid 2-ch1oro-5-(3-nitrobenzoyl)thiophene, m.p. 8699 C.

Analysis C H N Calculated for C H ClNO S: 49.3 2.3 5.2 Found: 49.1 2.5 4.8

EXAMPLE 2 This example illustrates the method for the preparation of intermediates of Formula 111 wherein Z is oxygen or sulfur.

A solution of bis(3-nitrophenyl)disulfide (30.8 g., 0.10 mole) in ethanol (100 ml.) at C. is treated with a mixture of sodium sulfide nonahydrate 12.0 g., 0.050 mole) and sodium hydroxide (8.0 g., 0.20 mole) dissolved in water, dropwise over 30 minutes. The mixture temperature is maintained for 30 minutes, then it is diluted with water (600 ml.), treated with decolorizing charcoal and acidified with hydrochloric acid. The organic product is separated and distilled at 126 C./1.5mm. This oil is taken up in percent ethanol and mixed with cuprous oxide (7.15 g., 0.050 mole) in ethanol (250 ml.) and heated at 85 to 90 C. overnight. The solid product, copper (1) 3-nitrothiophenol, is separated by filtration and dried.

A suspension of copper 3-nitrothiopheno1 (32.5 g., 0.15 mole), 3-bromothiophene (32.6 g., 0.20 mole), quinoline ml.) and pyridine (20 m.) is stirred at -180 C. for 20 hours. The mixture is poured into an ice-water-HC] mixture, then extracted with dichloromethane. The dichloromethane extracts are dried over magnesium sulfate and the solvent removed in vacuo. The residue is distilled to give 3-( 3-nitrophenylthio)thiophene, b.p. 203208 C./0.6 mm. which solidifies. Recrystallization from ethanol gives a solid, mp. 48.55 1C.

Found: 50.5 3.0 5.8

EXAMPLE 3 This example illustrates the method for the preparation of intermediates of Formula 111 wherein Z is a carbon-carbon bond.

A suspension of 3-nitroaniline (138 g., 1.0 mole) in thiophene (1 kg., 12 mole) is stirred vigorously while adding iso-amyl nitrite. The resulting slurry is heated 2 hours on the steam bath. After standing overnight the solid is separated by filtration and the filtrate is evaporated in vacuo to give a residue which is distilled, b.p. l50165 C. at 0.3 mm and solidifies. The 2-(3- nitrophenyl)thiophene is recrystallized from aqueous ethanol, m.p. 7073.5 C.

Analysis C H N Calculated for C ,H-,NO S: 58.54 3.44 6.83 Found: 58.7 3.6 6.8

EXAMPLE 4 Chloroform (250 ml.), 3-(5-chloro-2-thenoyl)aniline (7.5 g., 0.032 mole) and dimethylaniline (5.0 g., 0.034 mole) are stirred at C., while adding trifiuoromethanesulfonic anhydride (9.35 g., 0.034 mole). The solution is stirred at room temperature for 1 hour, then heated to and maintained at reflux temperature for 30 minutes after which the solvent and volatile impurities are removed in vacuo. The residue is extracted into 5 percent sodium hydroxide solution, the extracts are washed with hexane, then chloroform and finally acidified with 6N hydrochloric acid. The oil formed is extracted with diethyl ether, the extracts are dried over magnesium sulfate and the ether is removed in vacuo. The product solidifies on cooling and standing and is recrystallized from hexanebenzene to give 3- (5-chloro-Z-thenoyl)trifluoromethanesulfonanilide,

m.p.10l103 C.

Analysis C H N Calculated for C,,H-,ClF;,NO- ,S 39.1 1.9 3.8 Found: 39.5 2.1 3.8

EXAMPLE 5 To a solution of 4-ch1oro-3-(5-chloro-2thenoyl)- aniline (7.0 g., 0.026 mole) in dichloromethane (75 m1.) is added dimethylaniline (3.2 g., 0.026 mole) and the solution is cooled to about 0 C. Trifluoromethanesulfonic anhydride (7.3 g., 0.026 mole) is added dropwise with stirring while maintaining the temperature at 0 to 5 C. The mixture is stirred overnight, then the solvent and volatile by-products are removed in vacuo. The residue is treated with 5 percent sodium hydroxide solution, washed with dichloromethane, then hexane and finally neutralized with acetic acid. Purification is effected by elution chromatography followed by recrystallization from cyclohexane to give 4-chloro-3-(5-chloro-2- thenoyl)trifluoromethanesulfonanilide, m.p. 91-94 C.

Analysis C H N Culculutetl for C.,H..F,cl,No,s,= 35.7 1.5 3.5 Found: 35.8 1.6 3.5

EXAMPLE 6 Dichloromethane ml. 3-( 5ch1oro-2-thenoyl aniline (10.0 g., 0.042 mole) and dimethylaniline (5.1 g., 0.042 mole) are cooled to 0 C. and difluoromethanesulfonyl chloride (6.3 g., 0.042 mole) is added dropwise with stirring while maintaining the temperature below 5 C. The mixture is stirred overnight, then the solvent and volatile by-products are removed in vacuo. The residue is treated with 5 percent sodium hydroxide solution, washed with dichloromethane, then hexane, and finally neutralized with acetic acid. The 3-(5-chloro-2- thenoyl)difluoromethanesulfonanilide is recrystallized from ethanol-water, m.p. 1 121 14 Analysis C H N Calculated for C 2H9F2ClNo-3s2: 40.9 2.3 4.0 Found 41.2 2.3 4.0

EXAMPLE 7 Dichloromethane (100 ml.), 3-(3-thienylthio)ani1ine (14.6 g., 83.5 mmole) and triethylamine 12.5 ml.) are stirred at 0 C. while adding 14.2 ml. trifluoromethanesulfonic anhydride. The mixture is stirred overnight, and the mixture is treated with 10 percent sodium hydroxide. The basic mixture is steam distilled to remove volatile impurities and solvent. The residue is treated with decolorizing charcoal, then treated with hydrochloric acid to give an oil which is distilled, b.p. 204 C /2.2 mm. and analyzes correctly for 3-( 3-thienylthio)trifluoromethanesulfonanilide.

Analysis N Calculated for c un- No s 39.0 2.4 4.1 Found: 38.9 2.4 4.1

EXAMPLE 8 Dichloromethane (100 ml.), 3-(2-thieny1)aniline (11.6 g., 66 mmole) and triethylamine (10 ml.) are stirred at 0 C. under nitrogen. Trifluoromethanesulfonic anhydride 11.2 ml.) is added dropwise, the mixture is stirred overnight, and treated with 10 percent sodium hydroxide. The basic solution is steam distilled to remove volatile impurities, treated with decolorizing charcoal and acidified with hydrochloric acid. The residue is distilled, the main fraction boiling at C/1.6 mm. The product crystallizes and is recrystallized from trichloroethylene-hexane to give 3-(2-thienyl)trifluoromethanesulfonanilide, m.p. 69.57 1 C.

Analysis C H N Calculated for c,,H,F No s,; 43.05 2.6 4.6 Found: 42.9 2.7 4.8

EXAMPLE 9 A mixture of chloroform (25 ml.), 3-(2-thenoyl)- aniline (1.9 g., 0.009 mole) and dimethylaniline (1.2 g., 0.01 mole) is stirred at 0 C. and is maintained below 5 C. while adding chloromethanesulfonyl chloride (1.5 g., 0.009 mole) dropwise. The mixture is stirred at room temperature overnight, then refluxed for 2 hours. The solvent and volatile by-products are removed in vacuo and the residue is dissolved in 3 percent sodium hydroxide solution. This solution is washed with chloroform, then hexane and finally neutralized with acetic acid. The solid product is recrystallized from benzene-hexane to give 3-( 2- thenoyl)chloromethanesulfonanilide, m.p. 1 l21 14 A mixture of benzene (100 ml.), 3-(2-thienylthio)- aniline (l 1.8 g., 0.057 mole) and triethylamine (7 ml.) are stirred at C. while adding trifluoromethanesulfonic anhydride (9.4 ml.), then stirred overnight at room temperature. The mixture is treated with excess 10 percent sodium hydroxide solution, then steam distilled to remove volatile impurities. The organic residue is neutralized with hydrochloric acid and the product is distilled twice to give 3-(2-thieny1thio)- trifluoromethanesulfonanilide, b.p. b 1 52 C/0.1 mm.

Analysis C H N Calculated for C H,,F NO S;,: 39.0 2.4 4.1 Found: 38.7 2.5 4.0

EXAMPLE 1 l Analysis C H Calculated for C,,H,,F;,NO;.S,: 43.0 2.4 Found: 42.9 2.6

EXAMPLE 12 Dichloromethane 100 ml.), 3-(5-chloro-2-thenoyl)- aniline (8.5 g., 0.036 mole) and dimethylaniline (4.4 g., 0.036 mole) are stirred at 0 while adding fluoromethanesulfonyl chloride (4.8 g., 0.036 mole). The mixture is stirred overnight, then the solvent and volatile by-products are removed in vacuo. The residue is dissolved in 5 percent sodium hydroxide solution which is washed with dichloromethane, then hexane and finally neutralized with acetic acid. The precipitated 3-(5-chloro-2-thenoyl)fluoromethanesulfonanilide is recrystallized from ethanol-water, m.p. l22l24.5 C.

Analysis Calculated for C ,,H,F,c|No,s,=

Found:

EXAMPLE 1 3 Sodium methoxide (0.60 g., 0.01 1 mole) in methanol (250 ml.) and 3-( 2-thenoyl)trifluoromethanesulfonanilide (3.5 g., 0.0105 mole) is added. The solution is evaporated to dryness and the solid product, sodium 3-(2-thenoyl)trifluoromethanesulfonanilide, is dissolved in 1,2-dimethoxyethane. Methyl iodide (1.7 g., 0.012 mole) is added and the solution is heated to reflux temperature and maintained at this temperature for 1.5 hours. The solution is evaporated to dryness in vacuo to give an oil which gradually solidifies upon standing. Recrystallization from a dichloromethanehexane mixture gives N-methyl 3-(2- thenoyl)trifluoromethanesulfonanilide, m.p. 50 C. In the same manner N-methyl 3-(5-chloro-2- thenoyl)trifluoromethanesulfonanilide is prepared. Recrystallization from a dichloromethane-hexane mixture gives pure compound, m.p. 73-76 C.

The following compounds are prepared by reacting the sodium salt, prepared by the method described in Example 13, with the reactants listed in the table.

Reactants Product 69 Na 0 CN 0 9 ll 1 1| CF SOz-N- C S ClCN CFaSOzN- C s 0 ON 0 e n 1 i 1 i CF3SO2N- Q C S C1 CFaSOzN- C S 01 CHaS OzCl s 2011:

Q Na 0 G 11 I l 1 masons-E14, s/

s 010ml ll J Ferns 0,01 R 1 Tableo gnued Reactants Product r q Na C I g :1 cmcmr 9 1,50 Ne 1 c1 cF,s0,$' l5 01 1 f o i ClO 0 CHZCHS wherein R, is lower haloalkyl and at least one halogen is bonded to the alpha carbon atom or at least two halogens are bonded to a beta carbon atom, R is hydrogen, a pharmaceutically acceptable cation or lower alkyl, Y is hydrogen, lower alkyl, lower alkoxy, halogen or hydroxy, Y is hydrogen, lower alkyl or halogen and Z is carbonyl, O, S- or a single carbon-carbon bond.

2. A compound according to claim 1 wherein R is hydrogen.

3. A compound according to claim 1 wherein R is an alkali metal cation.

4. A compound according to claim 1 wherein R is trifluoromethyl.

5. A compound according to claim 1 wherein R, is difluoromethyl.

6. A compound according to claim 1 wherein Z is carbonyl.

7. A compound according to claim 6 wherein Y is hydrogen.

8. A compound according to claim 7 wherein Y is hydrogen.

9. A compound according to claim 7 wherein Y is halogen.

10. 3-(2-Thenoyl)trifluoromethanesulfonanilide according to claim 8.

1 l. 3-( 5-Chloro-2-thenoyl )trifluoromethanesulfonanilide according to claim 9.

12. 3-(5-Chloro-2-thenoyl)difluoromethanesulfonanilide according to claim 9.

13. A compound according to claim 6 wherein R, contains one carbon atom, R is hydrogen and Y and Y are hydrogen or halogen.

mmw emm @ER'NWQA'EE @E oohmmlou P tent No. 3,696,122 Mm October 3, 1972 Inventofls) Joseph Kenneth Harrington, George G-.I. Moore and John F. Gerster It is certified that error app e are in the ebove-Mentifiefi patent and that said Letters Patent are hereby correcte w shown below:

Column 1, line +5 in the formula:

" R 86 N I I ZUY' X r Z I should be --R SOZN S Column 3, lines 30-35 in the formula:

v Z-UY' HW" "R so w I N Z X Z s should be Column 11, line 23, "b. .,b152" should be --b. 152- Signed and sealed this-22nd day of May 1973.

(SEAL) Attest:

RD M.FLETCHER JR. ROBERT QOTTSCHALK ig iisting Officer; I l -wl lCommisslonegg gfi Patents FORM PO-iOSO (10-69) uscoMM-oc 00376-P69 1 \Li. GOVIINIIIIT "II'HIG OIIIC! ill! 0-3006 

2. A compound according to claim 1 wherein R is hydrogen.
 3. A compound according to claim 1 wherein R is an alkali metal cation.
 4. A compound according to claim 1 wherein Rx is trifluoromethyl.
 5. A compound according to claim 1 wherein Rx is difluoromethyl.
 6. A compound according to claim 1 wherein Z is carbonyl.
 7. A compound according to claim 6 wherein Y is hydrogen.
 8. A compound according to claim 7 wherein Y'' is hydrogen.
 9. A compound according to claim 7 wherein Y'' is halogen.
 10. 3-(2-Thenoyl)trifluoromethanesulfonanilide according to claim
 8. 11. 3-(5-Chloro-2-thenoyl)trifluoromethanesulfonanilide according to claim
 9. 12. 3-(5-Chloro-2-thenoyl)difluoromethanesulfonanilide according to claim
 9. 13. A compound according to claim 6 wherein Rx contains one carbon atom, R is hydrogen and Y and Y'' are hydrogen or halogen. 